Abstract
It has been hypothesized that neuroinflammation triggered during brain development can alter brain functions later in life. We investigated the contribution of inflammation to the alteration of normal brain circuitries in the context of neuroexcitotoxicity following neonatal ventral hippocampal lesions in rats with ibotenic acid, an NMDA glutamate receptor agonist. Excitotoxic ibotenic acid lesions led to a significant and persistent astrogliosis and microglial activation, associated with the production of inflammatory mediators. This response was accompanied by a significant increase in metabotropic glutamate receptor type 5 (mGluR5) expression within two distinct neuroinflammatory cell types; astrocytes and microglia. The participation of inflammation to the neurotoxin-induced lesion was further supported by the prevention of hippocampal neuronal loss, glial mGluR5 expression and some of the behavioral perturbations associated to the excitotoxic lesion by concurrent anti-inflammatory treatment with minocycline. These results indicate that neuroinflammation significantly contributes to long-lasting excitotoxic effects of the neurotoxin and to some behavioral phenotypes associated with this model. Thus, the control of the inflammatory response may prevent the deleterious effects of excitotoxic processes that are triggered during brain development, limiting the risk to develop some of the behavioral manifestations related to these processes in adulthood.
© 2010 Wiley-Liss, Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amphetamine / pharmacology
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Animals
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Animals, Newborn
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Anti-Inflammatory Agents / administration & dosage
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Behavior, Animal / drug effects
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Cells, Cultured
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Central Nervous System Stimulants / pharmacology
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Cytokines / metabolism
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Disease Models, Animal
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Encephalitis / diagnostic imaging
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Encephalitis / etiology
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Encephalitis / pathology*
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Encephalitis / prevention & control
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Enzyme-Linked Immunosorbent Assay / methods
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Female
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / physiology*
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Hippocampus / drug effects
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Hippocampus / pathology
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Ibotenic Acid / toxicity
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Interpersonal Relations
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Isoquinolines / pharmacokinetics
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Male
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Maze Learning / drug effects
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Microtubule-Associated Proteins / metabolism
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Minocycline / administration & dosage
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Motor Activity / drug effects
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Neuroglia / drug effects
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Neuroglia / metabolism*
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Neurons / metabolism
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Neurons / pathology
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Neurotoxicity Syndromes / complications*
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Neurotoxicity Syndromes / etiology
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Neurotoxicity Syndromes / pathology
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Phosphopyruvate Hydratase / metabolism
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Positron-Emission Tomography / methods
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Pregnancy
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Radioligand Assay / methods
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Rats
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate / genetics
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Receptors, Metabotropic Glutamate / metabolism*
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Tritium / pharmacokinetics
Substances
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Anti-Inflammatory Agents
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Central Nervous System Stimulants
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Cytokines
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Grm5 protein, rat
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Isoquinolines
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MAP2 protein, rat
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Microtubule-Associated Proteins
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate
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Tritium
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Ibotenic Acid
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Amphetamine
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Phosphopyruvate Hydratase
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Minocycline
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PK 11195